Malignant tumors of glial lineage are therapeutic challenges by virtue of relative inherent resistance to conventional cytolytic therapies and the innate proclivity of these cancer cells to invade into surrounding normal brain. Advances in extending median survival of glioma patients await strategies by which to control invasive tumor. The central hypothesis of this project is that local invasion by malignant glioblastoma cells is driven by specific and unique gene expression changes. Interference with the expression of these genes or interruption of the function of the gene products is likely to specifically target invasive glioblastoma cells, consequently impacting a major cause of tumor progression and recurrence. Success already realized from our use of laser capture microdissection and cDNA microarray analyses has generated candidate genes that have been validated in clinical specimens, and have undergone detailed cell and molecular biology experiments to determine the mechanism(s) by which candidate glioblastoma invasion genes activate the migratory or invasive process. Advances will be garnered through pursuit of 3 aims: The first aim is to sustain the discovery of candidate genes expressed or silenced in highly invasive glioblastoma cells compared to noninvading cells in the same tumor, and to place these candidate gene products into a functional matrix of aberrant signaling outcomes underlying invasion. The second aim is to validate candidate genes discovered in Aim #1 in the context of human glioblastoma invasion. The third aim is to determine the cellular and biochemical mechanisms of action of these genes and their matrix of aberrant signaling to discover points of convergence that serve as targets of vulnerability for therapeutic intervention. The sustained success of this project will assemble an understanding of genes driving the invasive phenotype of glioblastoma cells, discovering and validating crucial biochemical or regulatory linkages with other associated cell behaviors of proliferation and cell survival pathways. These findings will empirically elucidate those points of convergence in the pathways of the invasive phenotype that, when targeted by therapy, will most impact the malignant glial cell.